tbuckley/cabot-search huggingface dataset:
CTNI-31. TREATMENT BENEFIT IN PATIENTS AGED 80 YEARS OR OLDER WITH BIOPSY-PROVEN AND NON-RESECTED GLIOBLASTOMA IS DEPENDENT ON <i>MGMT</i> PROMOTER METHYLATION STATUS
Authors: Jonathan Weller, Sophie Katzendobler, Sebastian Niedermeyer, Patrick Harter, Jochen Herms, Christoph Trumm, Maximilian Niyazi, Niklas Thon, Joerg-Christian Tonn, Veit Stoecklein
Journal: Neuro-Oncology (2023)

Abstract PURPOSE Glioblastoma is associated with especially poor outcome in the elderly. It is unclear if patients aged ≥ 80 years benefit from tumor-specific therapy as opposed to receiving best supportive care (BSC) only. METHODS Patients with IDH-wildtype glioblastoma (WHO 2021), aged ≥ 80 years, and diagnosed by biopsy between 2010 and 2022 were included. Patient characteristics and clinical parameters were assessed. Uni- and multivariate analyses were performed. RESULTS 76 patients with a median age of 82 (range 80–89) and a median initial KPS of 80 (range 50–90) were included. Tumor-specific therapy was initiated in 52 patients (68%). 22 patients (29%) received temozolomide monotherapy, 23 patients (30%) were treated with radiotherapy (RT) alone and 7 patients (9%) received combination therapies. In 24 patients (32%), tumor-specific therapy was omitted in lieu of BSC. Overall survival (OS) was longer in patients receiving tumor-specific therapy (5.4 vs. 3.3 months, p&amp;lt;0.001). Molecular stratification showed that the survival benefit was owed to patients with MGMT promoter methylation (MGMTpos) who received tumor-specific therapy as opposed to BSC (6.2 vs. 2.6 months, p&amp;lt;0.001), especially to those with better clinical status and no initial polypharmacy. Patients with unmethylated MGMT promoter (MGMTneg) did not benefit from tumor-specific therapy (3.6 vs. 3.7 months, p=0.18). In multivariate analyses, better clinical status and MGMT promoter methylation were associated with prolonged survival (p&amp;lt;0.01 and p=0.01). CONCLUSION Benefit from tumor-specific treatment in patients with newly diagnosed glioblastoma aged ≥ 80 years might be restricted to MGMTpos patients, especially to those with good clinical status and no polypharmacy.
CTNI-11. THE VALUE OF STEREOTACTIC BIOPSY OF PRIMARY AND RECURRENT BRAIN METASTASES IN THE ERA OFPRECISION MEDICINE
Authors: Sophie Katzendobler, Anna Do, Jonathan Weller, Kai Rejeski, Mario Dorostkar, Nathalie Albert, Robert Forbrig, Maximilian Niyazi, Rupert Egensperger, Joerg-Christian Tonn, Louisa von Baumgarten, Stefanie Quach, Niklas Thon
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND: Brain metastases (BM) represent the most frequent intracranial tumors with increasing incidence. Many primary tumors are currently treated in protocols that incorporate targeted therapies either upfront or for progressive metastatic disease. In cases with diagnostic uncertainty, both in newly diagnosed or recurrent BM, stereotactic biopsy serves as an alternative to microsurgical resection particularly whenever resection is not deemed to be safe or feasible. This retrospective study aimed to analyze both diagnostic yield and safety of an image-guided frame based stereotactic biopsy technique (STX).
BIOM-16. LONGITUDINAL GLIOMA CEREBROSPINAL FLUID CELL-FREE DNA FOR MONITORING AND TREATMENT RESPONSE ASSESSMENT
Authors: Cecile Riviere-Cazaux, Xiaoxi Dong, Wei Mo, Shujun Luo, Amy Wang, Pan Du, Keyvan Ghadimi, Arthur Warrington, Terry Burns
Journal: Neuro-Oncology (2023)

Abstract Few methods exist via which to assess treatment response with high fidelity in gliomas. While CSF has previously been used as a source of cfDNA, it remains unknown how cfDNA abundance and sequencing changes throughout treatment and inevitable recurrence in gliomas. We utilized our biobank of longitudinal intracranial CSF specimens to determine the potential utility of CSF cfDNA as a monitoring tool for treatment response in patients with gliomas. Longitudinal CSF specimens were acquired via Ommaya reservoirs (NCT04692337) or ventriculoperitoneal shunts (NCT04692324) in patients with gliomas. cfDNA was extracted from 1-5 mL of CSF, and next-Generation sequencing or low-pass whole genome sequencing (LPWGS) was performed by Predicine, Inc. CSF acquired prior to versus after resection demonstrated an increase in quantified cfDNA (2.97x, range: 1.58-5.26x), consistent with the impact of increased parenchymal disruption and closer contact with CSF. Thereafter, CSF cfDNA continued to decrease throughout chemoradiation and adjuvant treatment and increased at recurrence, including in patients co-enrolled in immunotherapy trials for IL-7 agonists and pembrolizumab. Copy number burden (CNB) increased by the time of recurrence in three patients with known disease progression, and continued to decrease throughout immunotherapy treatment in one patient despite concerns of pseudoprogression. In one patient with a hypermutated glioblastoma, CSF cfDNA revealed over 59 genomic alterations, including MAP2K1, KIT, and PDGFRA, excluding even more variants of unknown significance, each of which had been detected in sequencing of the tissue acquired at resection and subsequently decreased with chemoradiation. In another patient with a known progressing EGFR-amplified GBM, over 200 new variants were identified by the patient’s final sample and EGFR copy number increased from 2 to over 30. In conclusion, cfDNA analysis over a patient’s disease course, including resection and treatment with standard-of-care and experimental therapies, may be of use for disease monitoring and treatment response.
CSIG-26. TARGETING HYPOXIC CANCER CELLS IN MEDULLOBLASTOMA
Authors: Yuki Kuranaga, Erwin Van Meir
Journal: Neuro-Oncology (2023)

Abstract The goal of this study is to thoroughly assess the role of hypoxia-induced transcription factors (HIFs) in MB growth and examine HIF as a potential therapeutic target. We first examined patient MB tumor by IHC and identified scattered areas with expression of HIF1a and HIF2a. We then established orthotopic human MB xenografts in mice and found hypoxic areas throughout the tumors using pimonidazole detection and they expressed both HIF1a, and HIF2a. There are only few observations of hypoxic areas within experimental MB. To explore the impact of HIFs on MB growth, we exposed MB cell lines (ONS-76; Shh and D556; Group 3) to 1% hypoxia in cell culture. We observed a decrease in cell growth, an increase in HIF1a and HIF2a protein expression, activation of HIF targets (Glut-1, VEGF), and a hypoxia-response element-driven luciferase reporter assay. To further examine the role of individual HIF isoforms, we employed CRISPR/Cas9 to knockout (KO) the HIF1a and/or HIF2a genes in ONS76 MB cells. The HIF reporter activity was partially canceled with single HIF-KO and completely abrogated with double KO and double KO reduced cell growth, indicating that both HIF-1 and HIF-2 are having roles for activating transcription and cell growth. Treatment of MB cells with 64B, an arylsulfonamide HIF/p300 inhibitor abrogated reporter activity by both HIF-1 and HIF-2 and reduced expression of hypoxia-induced genes. To investigate the potential of targeting HIF in vivo, we injected mice brains with wild-type and HIF1a/2a-KO ONS-76 cells and monitored their growth and survival. Mice injected with double KO HIF cells exhibited prolonged survival compared to those with parental cells (n = 5, p&amp;lt; 0.01). Further experiments to expand this approach with other MB cell line and test the anti-tumor effects of 64B in mice are ongoing. These findings support targeting HIFs as a novel therapeutic strategy in MB treatment.
CTIM-08. LOCAL IMMUNOTHERAPY WITH AUTOLOGOUS CIK CELLS FOR HIGH GRADE GLIOMAS: A PILOT STUDY WITH 20 YEARS FOLLOW-UP AND FAVORABLE FACTORS FOR LONG-TERM SURVIVAL
Authors: Hao Duan, Zhenqiang He, Zhongping Chen, Yonggao Mou
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Between November 2002 and March 2004, a pilot study was conducted to evaluate the tolerance and survival following local administration of autologous cytokine-induced killer (CIK) cells through Ommaya reservoirs implanted into the tumor resection cavity in 6 patients with high grade glioma (HGG) at Sun Yat-sen University Cancer Center. METHODS We reviewed the clinicopathological characteristics of these patients and updated their long-term follow-up. Profiles of tumor genome, transcriptome and immune microenvironment were also investigated by genomic target sequencing, RNA sequencing, electrochemiluminescence assay and immunohistochemistry (IHC) staining. RESULTS Four patients died from tumor progression and their overall survival ranged from 10.0 to 33.9 months. Remarkably, 2 patients, including one diagnosed as astrocytoma (IDH1 mutation, WHO 3) and the other diagnosed as diffuse hemispheric glioma H3 G34-mutant (G34-DHG), survived more than 19 years without evidence of recurrence. The distinctive clinical feature of the 2 long-term survivors was tumor gross total resection (GTR) before CIK therapy. Comparing with the short-term survivors, NTRK1 mutation was uniquely present and 353 genes were differentially expressed in the long-term survivors. These differential expression genes were highly associated with immune function. Electrochemiluminescence assay and IHC staining revealed higher expressions of cytokines and lower infiltrations of tumor-associated macrophages in the tumors of the long-term survivors. CONCLUSION These findings suggest that certain HGG patients can acquire long-term survival after local immunotherapy with CIK cells. Tumor GTR before CIK therapy and relatively weaker immunosuppressive tumor microenvironment may be the favorable factors for long-term survival.
CNSC-19. HYPOXIA-INDUCED NEURONAL ACTIVITY IN GLIOMA PATIENTS POLARIZES MICROGLIA BY POTENTIATING RNA M6A DEMETHYLATION
Authors: Xiaofan Guo, Qiu Wei, Gang Li
Journal: Neuro-Oncology (2023)

Abstract Neuronal activity in the brain has been reported to promote the malignant progression of glioma cells via nonsynaptic paracrine and electrical synaptic integration mechanisms. However, the interaction between neuronal activity and the immune microenvironment in glioblastoma (GBM) remains largely unclear. In this study, by applying chemogenetic techniques, we enhanced and inhibited neuronal activity in vitro and in a mouse model to study how neuronal activity regulates microglial polarization and affects GBM progression. Here, we demonstrate that hypoxia induces glioma stem cells (GSCs) to produce glutamate, which activates local neurons. The hypoxia-induced neuronal activity promotes GBM progression by facilitating microglial M2 polarization. We found that when microglia were co-cultured with activated neurons, the level of RNA m6A methylation in microglia was impaired, which subsequently induced microglial M2 polarization. In the mouse model, cortical neuronal activation promoted regional microglial M2 polarization while cortical neuronal inhibition decreased regional microglial M2 polarization in GBM xenografts. Together, these findings indicate that hypoxic GSC-induced neuronal activation promotes GBM progression by polarizing microglia via decreasing their m6A methylation levels.
EPCO-53. MULTI-SCALE REGULATION OF SIGNALING CASCADES AND TUMOR EVOLUTION IN HIGH GRADE ASTROCYTOMAS
Authors: Milan Chheda, Jingxian Liu, Song Cao, Kathleen Imbach, Marina Gritsenko, Tung-Shing Lih, Jennifer Kyle, Tomer Yaron, Yize Li, Ilya Strunilin, Zev Binder, Yi-Ting Wang, Chia-Feng Tsai, Weiping Ma, Lijun Chen, Natalie Clark, Matthew Wyczalkowski, Liang-Bo Wang, Nataly Al Deen, Wagma Caravan, Andrew Houston, Dmitry Rykunov, Sandra Cottingham, Rosalie Chu, Karl Weitz, Ronald Moore, Maciej Wiznerowicz, Galen Hostetter, Scott Jewell, Chelsea Newton, Karen Ketchum, Ratna Thangudu, Jill Barnholtz-Sloan, Pei Wang, David Fenyö, Eunkyung An, MacLean P Nasrallah, Mathangi Thiagarajan, Ana Robles, D R Mani, Richard Smith, Eduard Porta-Pardo, Lewis Cantley, Antonio Iavarone, Mehdi Mesri, Hui Zhang, Adam Resnick, Karin Rodland, Tao Liu, Li Ding
Journal: Neuro-Oncology (2023)

Abstract The National Cancer Institute Clinical Proteomic Atlas Consortium (CPTAC) herein reports our deep characterization of 228 grade IV IDH1 WT and mutant astrocytomas (including 28 matched primary and recurrent GBMs) using 15 proteogenomic and metabolomic platforms. Major advances over our first CPTAC GBM report (Wang et al., 2021, Cancer Cell), are the inclusion of many more samples including paired primary and recurrent tumors, application of new platforms, including glycoproteomics and targeted mass spectrometry methods, development and application of new computational techniques, and the integration of an atlas of experimentally determined, functional, kinase substrate interactions from Kinase Library. Paired primary-recurrent GBM analyses showed increased clonal diversity in recurrent tumors as a function of time, and treatment-induced mutation signatures. Proteomic and metabolomic analyses showed that different drivers can cause similar downstream effects. Only EGFR altered tumors were associated with dual EGFR glycosylation (N352 and N603) and EGFR phosphorylation (Y316) events. IDH1 mutation was associated with activated RTK signaling and decreased hypoxia pathway activities, concordant with epigenetic and metabolic profiles. Protein-protein interaction and kinase/phosphatase-substrate analyses uncovered detailed signaling events from different upstream drivers (e.g., EGFR, PDGFRA, and IDH1) converged through a PTPN11 hub to downstream effectors, including GAB1, IRS1, MAP3K5, and PTK2B. In summary, this multiscale resource presents new and deeper biological insights regarding treatment impact on tumor evolution, shared downstream consequences of independent drivers, and the potential importance of PTPN11 signaling circuitry across high-grade gliomas. We hope that reporting this new international resource to the SNO community will advance therapeutic development, including targeted therapies that may avoid known mechanisms of resistance.
PATH-52. MENINGIOMA MOLECULAR GROUPS PREDICT RESPONSE TO SURGERY AND RADIOTHERAPY
Authors: Justin Wang, Vikas Patil, Alexander Landry, Andrew Ajisebutu, Jeff Liu, Rebeca Yakubov, Andrew Gao, Aaron Cohen-Gadol, Christopher Wilson, Silky Chotai, Eric Holland, Jill Barnholtz-Sloan, Ghazaleh Tabatabai, Serge Makarenko, Stephen Yip, Felix Sahm, Sheila Mansouri, Qingxia Wei, Kenneth Aldape, Farshad Nassiri, Gelareh Zadeh
Journal: Neuro-Oncology (2023)

Abstract INTRODUCTION Aside from surgery, radiotherapy (RT) remains the only accepted treatment for meningiomas. However, patient selection for adjuvant RT remains controversial. We aimed to evaluate whether novel molecular and methylation groups could more accurately predict outcomes following surgery and adjuvant RT compared to WHO grade using a large clinical-molecular dataset. Method: We utilized publicly available, clinically annotated molecular datasets of meningiomas and generated de novo DNA-methylation and RNA-sequencing data. Meningiomas were classified into different molecular and methylation groups based on the methodologies of their original publications (Nassiri et al. [2021], Bayley et al.[2022], Choudhury et al.[2022], Sahm et al.[2017]) and progression-free survival (PFS) following surgery with and without adjuvant RT were analyzed. RESULTS A total of 2029 meningiomas from 11 different institutions with adjuvant RT data were included. Adjuvant RT was associated with improved PFS in WHO grade 1 meningiomas following subtotal resection(STR) and WHO grade 2 meningiomas following gross total resection(GTR) or STR. Multivariable analysis using Cox proportional hazards regression models showed that having a meningioma belonging to a hypermetabolic (MG3)(HR 3.63, 95%CI 1.47-8.99), or proliferative (MG4)(HR 7.24, 95%CI 2.84-18.49) molecular group were associated with worse PFS following surgery and adjuvant RT when controlling for age, gender, WHO grade, and extent of resection. Meningiomas belonging to DKFZ MC-intermediate, MC-malignant and UCSF hypermitotic methylation groups were also associated with worse outcomes. These relationships held true even in subgroup analysis with only WHO grade 2 meningiomas and following propensity score matching for the same clinical covariates above. Nearly all molecular and methylation classifications predicted 5-year PFS including following surgery and adjuvant RT (area under the curve [AUC] 0.61-0.72) better than WHO grade (AUC 0.51). CONCLUSIONS Molecular classification improves clinical outcome prediction for meningiomas following surgery and adjuvant radiotherapy, supporting the rationale for molecularly informed treatment decisions and potential clinical trial stratification.
NIMG-87. PEDIATRIC BRAIN TUMOR SEGMENTATION INITIATIVE AT CHILDREN’S BRAIN TUMOR NETWORK (CBTN); PROJECT UPDATE ON IMPROVED PERFORMANCE AND FUTURE PROSPECTS
Authors: Anahita Fathi Kazerooni, Nastaran Khalili, Debanjan Haldar, Karthik Viswanathan, Ariana Familiar, Sina Bagheri, Hannah Anderson, Aria Mahtabfar, Phillip Storm, Christos Davatzikos, Adam Resnick, Jeffrey B Ware, Arastoo Vossough, Ali Nabavizadeh
Journal: Neuro-Oncology (2023)

Abstract Pediatric brain tumors (PBT) exhibit significant heterogeneity, and accurate assessment of tumor response is crucial for patient management. While bidimensional measurements of tumor size are commonly used, they may underestimate tumor dimensions. Our group previously developed a multi-institutional, and multi-histology model on the Children’s Brain Tumor Network (CBTN) imaging dataset to segment tumor subregions, recommended by the Response Assessment in Pediatric Neuro-Oncology (RAPNO) working group. In the most recent update, we utilized a self-configuring deep learning architecture called nnU-Net on a large dataset of well-annotated PBTs (233 training, and 60 withheld internal and 46 external test sets). The model was trained and validated on multiparametric MRI sequences and differentiated various tumor subregions, including enhancing tumor (ET), nonenhancing tumor (NET), edema (ED), and cystic component (CC) and the whole tumor (WT) regions. Clinical validity was assessed by comparing the volumes of tumor subregions predicted by the model with expert manual segmentations, demonstrating strong agreement, with statistically significant Pearson’s correlation coefficients of 0.93/0.69 for ET, 0.94/0.93 for NET, 0.78/0.93 for CC, and 0.94/0.50 for ED subregions (p&amp;lt; 0.001) for the internal/external test cohorts. The trained model showed excellent performance for the withheld internal test set and decent accuracy for the external test set. Median Dice scores for internal/external test sets were 0.94±0.10/0.90±0.07 for WT, 0.85±0.33/0.84±0.30 for ET, 0.80±0.32/0.64±0.31 for NET, 0.79±0.37/0.67±0.33 for CC, 0.70 ±0.42/0.37±0.43 for ED, and 0.86±0.19/0.80±0.21 for all nonenhancing components (combination of NET, CC, and ED), respectively. The proposed automated segmentation method provides accurate and reproducible volumetric measurements of RAPNO-defined subregions in PBTs. It exhibits robust performance and potential generalization to external datasets and the accuracy is higher compared to the previous DeepMedic model. We will continue to improve the model by constantly adding new training data to further improve the performance and sustain model robustness.
IMMU-38. INTRATUMORAL CORRELATION OF MULTIPLEX IMMUNOFLUORESCENCE AND89ZR-CREFMIRLIMAB BERDOXAM IMMUNOPET IN RECURRENT GBM PATIENTS TREATED WITH NEOADJUVANT ANTI-PD-1 +/- ANTI-CTLA-4 THERAPY
Authors: Lauren Markus, Lu Sun, Willy Hugo, Annick D Van den Abbeele, Patrick Wen, Robert Prins
Journal: Neuro-Oncology (2023)

Abstract Glioblastoma (GBM) is a highly aggressive brain tumor that responds poorly to checkpoint blockade inhibitors (ICIs), such as anti-PD-1. We previously reported that neoadjuvant anti-PD-1 therapy activated and recruited T cells into recurrent GBM (rGBM) tumors, but also increased immune checkpoint interactions between T cells and myeloid cells. To overcome this resistance mechanism, we are currently conducting a phase 1B clinical trial of neoadjuvant anti-PD-1 (Nivolumab, BMS) +/- anti-CTLA-4 (Ipilimumab, BMS) combination therapy for rGBM patients (NCT04606316). To evaluate the systemic and local tumor microenvironment effects of these checkpoint inhibitors, we used immuno-positron emission tomography (CD8 immunoPET, 89Zr-crefmirlimab berdoxam, ImaginAb) to track CD8+ T cells in five rGBM patients before and after neoadjuvant anti-PD-1 or combination therapy with anti-CTLA-4, and used multiplex immunofluorescence (mIF) to analyze the intratumoral immune profile of patient-matched tumors. We found that CD8 ImmunoPET imaging could detect physiologic tracer uptake in the lymph node basins and tumor bed prior to and following checkpoint blockade, suggesting a systemic immunometabolic response within the tumor after therapy. Correlation with mIF found that combination therapy (n=1) increased the density of conventional type 1 and 2 dendritic cells (cDC1: CD3-CD141+XCR1+ and cDC2: CD3-CD1c+) in the tumors, especially cDC1, compared to anti-PD-1 monotherapy (n=4) or untreated patients (n=3) (the densities of cDC1 and cDC2 cells were 163 cells/mm2 and 13.3 cells/mm2 respectively). Moreover, combination ICI therapy was associated with enhanced infiltration of CD8+ and CD4+ T cells in the tumor (28.7 cells/mm2 and 73.8 cells/mm2, respectively) with a specific increase in CD4+ T cells compared to anti-PD-1 monotherapy. In summary, preliminary results of the correlation of the longitudinal brain immunoPET imaging with the intratumoral mIF analysis in these five rGBM patients suggests distinct effects of monotherapy vs. combination neoadjuvant anti-PD-1 and anti-CTLA-4 therapy on the intratumoral immunometabolic profile of rGBM patients.
NIMG-55. PREDICTING SITES OF TUMOR PROGRESSION IN THE INVASIVE MARGIN OF GLIOBLASTOMAS (PRAM-GBM STUDY): AN INTERIM ANALYSIS OF A MULTI-CENTER IMAGING BIOMARKER STUDY
Authors: Stephen Price, Roxanne Mayrand, Yizhou Wan, Lynn Cream, Julia Cook, Alimu Dayimu, Michael Jenkinson, Anil Varma, Keyoumars Ashkan, Simon Thomson, Stuart Smith, Nikolaos Demiris, Tomasz Matys, Chao Li
Journal: Neuro-Oncology (2023)

Abstract INTRODUCTION Although glioblastoma cells extend throughout the brain, virtually all patients die from local progressive disease. This progressive tumor occurs at the resection margins and usually within the high-dose radiotherapy field. If we could identify where the tumor would progress, we could consider personalizing radiotherapy and surgical targets. Previous work has shown diffusion tensor MR as a potential biomarker of occult invasion. Biopsy studies reveal that the q-anisotropic component correlates with high-density tumor, and the extent of resection correlates with improved survival. We hypothesize that this is a biomarker that can predict where glioblastomas may progress. STUDY DESIGN: A multicentre, pragmatic, longitudinal observational cohort study from 6 centers. This is a planned interim analysis of the first cohort. METHODS Patients with glioblastomas suitable for maximal resection were imaged pre-operatively with a diffusion tensor MRI protocol. This was processed using a tensor decomposition method to generate the q-anisotropic component. Masks of the abnormal q-component were overlaid on the masks of new areas of contrast enhancement at progression (ground truth). Intersecting voxels were classified as true positive, true negative, false positive, and false negative, and the sensitivity and specificity were calculated. RESULTS 139 patients were recruited, but 50 were withdrawn. The interim analysis was planned for the first 2/3rds of the cohort (55 patients). Combining q and contrast enhancement provided the best predictor of site of tumor progression with a mean sensitivity of 79% [95%CI: 71-88%] compared to contrast enhancement of only 50% [95%CI: 39-61%]. Specificity remained high in both groups (CE+q mean 94% [95%CI: 93-95%] vs. CE alone 98% [95%CI: 97-98%]). CONCLUSION The anisotropic diffusion component, q, provides the best biomarker for identifying ‘residual tumor.’ This biomarker will form the basis of an early phase surgical trial IDEAL Stage 1 and 2a study to change surgical resection target.